US2011190383A1PendingUtilityA1

Diagnostic, Prognostic and Therapeutic Uses of MIRs in Adaptive Pathways and/or Disease Pathways

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Assignee: UNIV OHIO STATEPriority: Sep 18, 2008Filed: Sep 18, 2009Published: Aug 4, 2011
Est. expirySep 18, 2028(~2.2 yrs left)· nominal 20-yr term from priority
Inventors:Clay B. MarshMelissa G. PiperDuaa A. Dakhlallah
A61P 9/00C12Q 2600/136C12Q 2600/178C12Q 1/6883C12Q 2600/158A61P 17/00
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Claims

Abstract

Described herein are methods and compositions for the diagnosis, prognosis and treatment of various adaptive and/or of disease pathways by examining samples containing one or more miRs therein, and by formulating therapeutic agents therefrom.

Claims

exact text as granted — not AI-modified
1 . A method of diagnosing or detecting susceptibility of a subject to one or more of a condition characterized by injury and tissue repair that transiently or permanently results in changes in one or more of an adaptive pathways and/or disease pathways,
 wherein the disease pathway comprises lung fibrosis, including idiopathic pulmonary fibrosis (IPF) associated disease or an interstitial lung disease (ILD),   
       the method comprising:
 determining the level of at least one miR gene product in the miR-17˜92 cluster in a sample from the subject, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92; and 
 comparing the level of at least one miR gene product in the sample to a control, 
 wherein an alteration in the level of the at least one miR gene product in the sample from the subject, relative to that of the control, is diagnostic or prognostic of such disease. 
 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the miR comprises miR-19b. 
     
     
         8 . The method of  claim 7 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the control is selected one or more of:
 a reference standard;   the level of the at least one miR gene product from a subject that does not have the disease; and   the level of the at least one miR gene product from a sample of the subject that does not exhibit such disease.   
     
     
         11 . The method of  claim 1 , wherein the subject is a human. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . A method of inhibiting progression or proliferation of idiopathic pulmonary fibrosis associated disorder in a subject, comprising:
 introducing into at least one cell of the subject one or more agents which alter expression and/or activity of at least one miR in the miR-17˜92 cluster within the cell, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92, and   maintaining the cells under conditions in which the one or more agents: inhibits expression or activity of the miR; enhances expression or activity of one or more target genes of the miR; or, results in a combination thereof, thereby inhibiting progression or proliferation of the disease or disorder.   
     
     
         15 . The method of  claim 14 , wherein the miR comprises miR-19b. 
     
     
         16 . The method of  claim 15 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         17 . The method of  claim 14 , wherein the cell is a human cell. 
     
     
         18 . A method of identifying a therapeutic for to, idiopathic pulmonary fibrosis (IPF) agent, comprising:
 providing a test agent to a cell and measuring the level of at least one miR in the miR-17˜92 cluster associated with an altered expression levels in the cells, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92,   wherein an alteration in the level of the miR in the cell, relative to a suitable control cell, is indicative of the test agent being a therapeutic agent.   
     
     
         19 . The method of  claim 19 , wherein the miR comprises miR-19b. 
     
     
         20 . The method of  claim 19 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         21 . A method for regulating levels of one or more proteins in a subject having, or at risk of developing idiopathic pulmonary fibrosis (IPF) associated disorder, wherein the at least one protein comprises one or more of: c-myc, CTGF, TSP1, HDAC4, the method comprising:
 altering the expression of at least one miR gene product in the miR-17˜92 cluster lung cells in the subject, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92.   
     
     
         22 . The method of  claim 21 , wherein the miR comprises miR-19b. 
     
     
         23 . The method of  claim 22 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 21 , wherein the subject has idiopathic pulmonary fibrosis (IPF). 
     
     
         27 . The method of  claim 21 , wherein the subject has an interstitial lung disease (ILD). 
     
     
         28 . A method for assessing prognosis in a subject with idiopathic pulmonary fibrosis associated disorder, comprising:
 determining an level of at least one miR in the miR-17˜92 cluster which alters expression of one or more of the protein levels of for c-myc, CTGF and HDAC4 as a prognostic indicator of disease progression, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92.   
     
     
         29 . The method of  claim 28 , wherein the miR comprises miR-19b. 
     
     
         30 . The method of  claim 29 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         31 . (canceled) 
     
     
         32 . A method for assessing prognosis in a subject with idiopathic pulmonary fibrosis- or ILD-associated disorder, comprising:
 determining an altered expression of one or more of the protein levels as a prognostic indicator of disease progression,   wherein the at least one protein comprises one or more of: c-myc, CTGF, TSP1, HDAC4, wherein at least miR-19b and mir20a are down regulated with increasing severity of disease in patients with IPF.   
     
     
         33 . The method of  claim 32 , wherein the miR comprises miR-19b. 
     
     
         34 . The method of  claim 33 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         35 . A method for altering the expression of a target gene in a subject having, or at risk or developing idiopathic pulmonary fibrosis (IPF), comprising: inducing expression of one or more miRs in the miR-17˜92 clusters in cells in the subject, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92. 
     
     
         36 . The method of  claim 35 , wherein the miR comprises miR-19b. 
     
     
         37 . The method of  claim 36 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         38 . The method of  claim 37 , comprising inducing expression by transient transfection in IPF fibroblast cells in the subject sufficient to alter expression of at least one target and/or to change at least one gene networks, to expression those present in normal fibroblast cells, wherein one or more miRs of the miR-17˜92 cluster downregulate expression of one or more genes selected from: CTGF, TGFβ, MMPs, VEGF, Col1a, and thrombospondin-1 (TSP1). 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . A method for treating idiopathic pulmonary fibrosis (IPF) fibroblasts in lung cells in a subject, comprising introducing one or more miRs in the miR-17˜92 cluster into the cells in an amount sufficient to recover a proliferative and younger phenotype in the cells, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92. 
     
     
         42 . The method of  claim 41 , wherein the miR comprises miR-19b. 
     
     
         43 . The method of  claim 42 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         44 . A method for enhancing wound healing in lung cells a subject having or at risk of developing a fibrotic disease of an organ, including but not limited to, idiopathic pulmonary fibrosis (IPF) or facilitating wound repair in an adaptive setting, comprising transfecting cells with one or more miRs in the miR-17˜92 cluster, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92. 
     
     
         45 . The method of  claim 44 , wherein the miR comprises miR-19b. 
     
     
         46 . The method of  claim 45 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b. 
     
     
         47 . The method of  claim 44 , wherein the cells comprise lung cells. 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . (canceled) 
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . A method for detecting changes in myofibroblast production and/or detecting alterations in epithelial cell-to-mesenchymal cell transition in a subject having, or at risk of developing idiopathic pulmonary fibrosis (IF), comprising measuring levels of one or more miRs in the miR17˜92 cluster in lung cells in the subject, wherein the miR-17˜92 cluster comprises miR-19b, miR-17-3p, miR-17-5p, miR-18a, miR19a, miR-20a and miR-92. 
     
     
         69 . The method of  claim 68 , wherein at least one of miR-19b and miR-20a are down regulated with increasing severity of disease in patients with a fibrotic disease of an organ, including but not limited to IPF. 
     
     
         70 . The method of  claim 68 , wherein the miR comprises miR-19b. 
     
     
         71 . The method of  claim 70 , wherein at least one other miR in the miR-17˜92 cluster is used in combination with miR-19b.

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